Glycogen synthase kinase-3 (GSK3) has widespread regulatory effects on cell signaling pathways and behavioral phenotypes associated with psychiatric diseases. Furthermore, GSK3 is a feasible therapeutic target because the GSK3 inhibitor lithium is already widely used as a treatment for bipolar disorder and many new small molecule selective GSK3 inhibitors are under development. Three specific aims will address important actions of GSK3 in cell signaling responses to stress, developmental changes in GSK3, and the role of GSK3 in behavioral responses to stimulants in young and adult mice. These goals will not only provide important information about these links between GSK3 and psychiatric illnesses, but will also provide the candidate with multidisciplinary training important for her career plans to establish an independent research laboratory focused on biomedical problems in biological psychiatry. Endoplasmic reticulum (ER) stress, resulting from the accumulation of misfolded proteins, is associated with many diseases and activates both the UPR (unfolded protein response) and autophagy. These responses can allow cells to adapt and survive stress, or can lead to cell death, and inhibitors of GSK3 promote cell adaptation and reduce cell death, but the mechanisms for these regulatory actions are unclear. Specific Aim 1 will test the mechanisms by which GSK3 regulates the UPR and the balance between autophagy and apoptosis in ER stress. Many psychiatric diseases are initiated during development, and there has recently been a rapid increase in the prevalence of psychiatric diseases in young persons, particularly in attention-deficit/hyperactivity disorder (ADHD). However, it is unclear what predisposes young people during development to many major psychiatric diseases, such as ADHD, and if drugs administered during development have equivalent effects as in adults, where most testing was conducted. Of particular interest is the prevalent use of stimulants that activate dopaminergic signaling in the treatment of ADHD. Our laboratory has shown that 3 week old and 5 week old mice have much higher levels of GSK3 in the brain than adult mice, suggesting this may play a role in regulating developmental susceptibilities, and alter responses to dopaminergic stimulants that activate GSK3. Specific Aim 2 will test in mouse brain the developmental changes in GSK3 and its regulation by stimulants. Dopamine-mediated hyperactivity induced by amphetamine treatment is completely blocked by GSK3 inhibitors, signifying that activation of GSK3 following amphetamine is critical for this behavioral response. Specific Aim 3 will test in mice the role of GSK3 in mediating behavioral responses to stimulants during development compared with adult mice. Altogether, these goals will provide multidisciplinary training and will address topics critical for understanding the regulatory roles of GSK3 in cellular signaling in response to stress, during development, and in response to stimulants that are widely used in pre-adults. PUBLIC HEALTH RELEVANCE: Mental health disorders are the leading cause of disability in the United States, accounting for 25 percent of all years of life lost to disability and premature mortality (NIMH Strategic Plan, 2008). Progress in reducing the prevalence and severity of mental disorders requires coalescence of multiple strategies. Among these are understanding biochemical mechanisms that impair cellular functions, mechanisms controlling vulnerability, and behavioral outcomes of interventions, each of which is addressed by the three Specific Aims of this project.